The class of anti-diabetic drugs called biguanides originates from the Galega officinalis plant, which has been known for several centuries for its capacity to reduce the symptoms of diabetes mellitus. Metformin is a compound derived from biguanides that primarily acts by reducing hepatic gluconeogenesis, but also reduces glucose absorption at the gastro-intestinal tract level and increases sensitivity to insulin by increasing the peripheral utilisation of glucose. This may be due to the fact that metformin improves the binding of insulin to its cellular receptor, which is explained by the increased activity that it induces in the tyrosine kinase postreceptor and the consequent increase in the number and activity of GLUT4 carriers.
Metformin is not metabolized; it is directly excreted in the urine. Its half-life is 6.2 hours.
Metformin and metformin hydrochloride have poor intestinal absorption at the colon and the lower gastro-intestinal tract level.
This invention relates to the development of a new biguanide salt based on metformin conjugated with Glycine, which exhibits a better absorption and passage into the bloodstream, less gastro-intestinal adverse effects and a better pharmacokinetic profile as compared to other metformin salts known in the prior art.
One disadvantage of metformin hydrochloride is that it is hygroscopic. This hinders the industrial handling thereof to prepare solid compositions such as tablets, capsules, etc. Moreover, in its solid form, it is a corrosive crystal, which wears the tabletting machines used. Furthermore, it is an extremely bitter salt for users and the acid generated thereby often causes gastric disorders with prolonged use.
Patent GB 1473256 discloses, for the first time, biguanide salts for treating metabolic disorders, especially diabetes mellitus, by reducing blood glucose levels, with the following formula:
where R1 represents a hydrogen atom or a lower alkyl or a lower alkenyl group and R2 represents a lower alkyl, aryl, aryl-(lower alkyl), or an aryloxy-(lower alkyl) group or R1 and R2 together represent a lower alkenyl group, R3 represents a hydrogen atom or a group with the formula:

Where R4 and R5 each represent a hydrogen atom or a cation or R4 represents a hydrogen and R5 represents a lower alkyl group, or R4 and R5 together represent a lower alkylene group, and n means 1 or 2.
Unlike other biguanides, such as buformin or phenformin, metformin does not cause lactic acidosis at high serum levels. Metformin hydrochloride is the currently marketed salt and has the following formula:

Belgian patent BE 568,513 discloses acid addition salts of metformin, including metformin hydrochloride. Patent application US 2005/0158374 discloses metformin associated with fatty acids, with improved absorption at the gastro-intestinal tract level. This metformin associated with a fatty acid (such as laureate, succinate, caprate, palmitate, etc.) is produced from a metformin salt (for example, metformin-HCl). These compounds were created in order to increase absorption at the lower gastro-intestinal tract level and for the drug to remain in the blood of patients who so require at relatively constant levels throughout the day, which avoids the intake of several daily doses. The plasma concentrations of these compounds measured in rats in ηg/ml with respect to time in hours show a greater bioavailability than metformin salts which are not bound to fatty acids. However, unlike metformin-fatty acid compounds, metformin glycinate not only reaches the maximum plasma level within the first few minutes, but these same levels remain in plasma in a sustained manner for the first 3 to 4 hours, with a gradual decrease for 10 hours following intake. (FIG. 1)
This phenomenon exhibited by metformin glycinate is particularly advantageous to reduce glycemia, due to the high concentrations that it reaches in the first hour and which may be particularly useful in dealing with postprandial hyperglycemia, which has been recognized as one of the main factors for cardiovascular risk and vascular damage. On the other hand, since it reaches higher maximum concentrations than metformin hydrochloride, metformin glycinate requires lower doses to produce similar hypoglycaemic effects.
Another document that pertains to the state of the art is European patent EP 1039890 from Bristol-Myers Squibb Company, which addresses various dicarboxylic acid salts of metformin, in combination with another anti-diabetic agent, and a metformin fumarate, metformin succinate and metformin maleate. Similarly, there are other patents in the state of the art that relate to metformin salts, such as U.S. Pat. No. 4,835,184, which discloses the p-chlorophenoxyacetic salt of metformin, French patents FR 2320735 and FR 2037002, which disclose the pamoate salt of metformin, U.S. Pat. No. 3,957,853, which discloses the acetylsalicylate salt of metformin, German patents DE 2357864 and DE1967138, which disclose the nicotinic acid salt of metformin, Japanese patent JP 64008237, which discloses hydroxyacid salts of metformin, including salts of hydroxy-aliphatic dicarboxylic acids, such as mesotartaric acid, tartaric acid, mesoxalic acids and oxidised maleates; it may be observed that all these are organic acid salts of metformin.
In this invention, a new 1,1-dimethylbiguanide Glycinate salt was synthesized, called Metformin Glycinate. This salt exhibits advantages over other Metformin salts. These advantages are due, in the first place, to the fact that the glycine counterion exhibits hypoglycemic effects by itself. Moreover, this salt exhibits more rapid absorption, reaching higher plasma concentrations than those produced with metformin hydrochloride (FIG. 1). On the other hand, the glycine that is generated when the salt is ionized is not a strong acid; consequently, undesirable gastric effects are reduced. Finally, metformin glycinate has favorable physical characteristics for industrial-scale handling, thus facilitating the preparation of pharmaceutical compositions, since it is less corrosive, has better rheological properties and is less susceptible to compacting.
The synthesis was synthesized from the Metformin Hydrochloride salt, where free Metformin was produced by releasing the hydrochloride counterion, using an ion-exchange column for this purpose; the Metformin base released was dissolved in an aqueous medium and, subsequently, glycine was added at ambient temperature under constant stirring; subsequently, the resulting product is heated until a concentrated solution is produced, an organic solvent is added which does not react with the components present and wherein glycine is insoluble in order to create insolubility in the medium and favor crystallization of the saturated medium; all this in order to precipitate the excess glycine and then separate it by filtering; the filtrate was concentrated again until precipitation of the metformin glycinate salt was achieved.